6/11/2025
Nature medicine
T and B cell responses against Epstein-Barr virus in primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein-Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3-22.9), suggesting a link between EBV and PSC.
20/02/2024
Cell reports. Medicine
Merkel cell polyomavirus-specific and CD39+CLA+ CD8 TÊcells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma
Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 TÊcells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific TÊcell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 TÊcells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39+CLA+ CD8 TÊcell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39+CD103+ CD8 TÊcells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific TÊcells.
20/02/2024
Cell reports. Medicine
Merkel cell polyomavirus-specific and CD39+CLA+ CD8 T cells as blood-based predictive biomarkers for PD-1 blockade in Merkel cell carcinoma
Merkel cell carcinoma is a skin cancer often driven by Merkel cell polyomavirus (MCPyV) with high rates of response to anti-PD-1 therapy despite low mutational burden. MCPyV-specific CD8 T cells are implicated in anti-PD-1-associated immune responses and provide a means to directly study tumor-specific T cell responses to treatment. Using mass cytometry and combinatorial tetramer staining, we find that baseline frequencies of blood MCPyV-specific cells correlated with response and survival. Frequencies of these cells decrease markedly during response to therapy. Phenotypes of MCPyV-specific CD8 T cells have distinct expression patterns of CD39, cutaneous lymphocyte-associated antigen (CLA), and CD103. Correspondingly, overall bulk CD39+CLA+ CD8 T cell frequencies in blood correlate with MCPyV-specific cell frequencies and similarly predicted favorable clinical outcomes. Conversely, frequencies of CD39+CD103+ CD8 T cells are associated with tumor burden and worse outcomes. These cell subsets can be useful as biomarkers and to isolate blood-derived tumor-specific T cells.
13/01/2023
eLife
Multimodal HLA-I genotype regulation by human cytomegalovirus US10 and resulting surface patterning
To control human cytomegalovirus (HCMV) infection, NK cells and CD8+T-cells are crucial. HLA class I (HLA-I) molecules play a central role for both NK and T-cell responses and are targets of multifaceted HCMV-encoded immunoevasins. A so far insufficiently studied HLA-I immunoevasin is the glycoprotein US10. It was shown that US10 targets HLA-G, but it is unknown whether US10 contributes also to escape from classical HLA-I antigen presentation. Our biochemical analysis revealed that early during maturation, all investigated HLA-I (HLA-A/B/C/E/G) heavy chains are recognized and bound by US10. Remarkably, the consequences of this initial binding strongly depended on both the HLA-I geno- and allotypes: i) HLA-A molecules escaped down-regulation by US10, ii) tapasin-dependent HLA-B molecules exhibited impaired recruitment to the peptide loading complex and maturation, iii) HLA-C and HLA-G, but not HLA-A/B/E, strongly bound US10 also in their β2m-assembled form. Thus, US10 senses geno- and allotypic differences in a so far unparalleled and multimodal manner, suggestive of adaptation to HLA-I genotype differences. At a further level of complexity, in HCMV-infected fibroblasts inhibition of overlappingUS10andUS11transcription revealed an additional HLA-I specificity, suggesting targeting of HLA-I in a synergistically arranged manner. Our study unveils the exceptional HLA-I selectivity of HCMV-encoded US10 and underlines its contribution to immune escape.